Diabetes (Diabetes Mellitus, DM) is a common metabolic endocrine disease. It is a clinically chronic and systemically metabolic syndrome, characterized by chronic hyperglycemia, disturbance of carbohydrate, fat and protein metabolism resulting from absolute or relative insulin deficiency, or insensitivity of the target tissues to insulin. It is caused by the interaction of genetic and environmental factors, involving various body systems, including cardio-cerebrovascular, kidney, eye, nerve, and other organ complications. It's a lifelong disease, and is seriously harmful to human health.
Diabetes is a common, frequently occurring disease, and it has become the third largest common disease threatening human lives following cancer and cardiovascular disease. It is a challenge to the world. DM is harmful to people's health regardless of race and nation. According to the statistics from the International Diabetes Federation (IDF), during the ten years from the mid-1980s to the mid-1990s of the last century, the total number of diabetics increased 4-fold, up to 120 million. In 2007, the global number of diabetics was 246 million, of which 46% were 40-59 years old and of the labor force population. It is anticipated that in 2025, the global number of diabetics will increase to 380 million, accounting for 7.1% of the global adult population.
According to the data announced by ADA (American Diabetes Association) in January 2011, there are 25.6 million diabetics in the United States, accounting for 8.3% of the U.S. population. Among the huge medical cost in the United States, one of every 10 dollars is spent on diabetes. In China, the number of diabetics increased significantly for the past 20 years. Epidemiological investigations revealed the prevalence of diabetes was less than 4% before 2002. Recently, a national epidemiological survey of diabetes showed that the prevalence of diabetes among Chinese adults (20 years of age or older) is more than 10%. The overall prevalence of diabetes was 9.7%. Currently, there are more than 92 million people suffering from diabetes, and another 100 million and 5000 people will become diabetics. China is becoming the country having the largest number of diabetic patients, instead of India.
Diabetes is mainly divided into insulin-dependent diabetes mellitus (type I diabetes), insulin-independent diabetes mellitus (type II diabetes), as well as other special types of diabetes. Type I diabetes mainly occurs in children and adolescents, the peak age is 12 years old, accounting for less than 10% of diabetics. Type II diabetes mainly occurs in adults, accounting for more than 90% of diabetics. The exact pathological mechanisms underlying diabetes is still unknown, there is no cure for diabetes. Currently, therapy for diabetes focuses on drug treatment and control. For a small portion of patients suffering from type II diabetes, diet and exercise therapy can be used to control the condition, whereas for the vast majority of patients, drug therapy is necessary. Drug therapy includes Chinese medicine and chemical medicine. Chemical medicine is predominant, and is divided into two categories: protein and polypeptide drugs as represented by insulin and analogues thereof, and small molecule anti-diabetic drugs for oral administration.
With the dramatic increase in the number of diabetic patients worldwide, the global diabetes drug market is also rapidly growing. According to statistics, in 2005 the diabetes drug market reached $18.6 billion, an increase of 11.5% compared to the previous year. In 2006, it was $21.2 billion, an increase of 14%. In 2007, it was $24.1 billion, an increase of 13.7%, ranking fifth in the global pharmaceutical market. 15 to 20 percent annual growth rate is predicted. Research and Markets reports that insulin and analogues thereof account for 40.1% of the total diabetes drug market, oral hypoglycemic drugs account for 58%, and other drugs share the remaining 1.9%.
A series of patent applications have disclosed some insulin analogues, which comprise amino acid substitutions at various sites of natural human insulin sequences. European Patent EP0425482B1 discloses an insulin analogue having a histidine (His) or tyrosine (Tyr) substitutions at position B25. European Patent EP0419504B1 discloses an insulin analogue having a substitution at position B3, and simultaneously having a glutamine (Gln) substitution at A5 or A15, or alternatively, an asparagine (Asn) substitution at A21 or A18. U.S. Pat. No. 5,008,241A discloses an insulin analogue having a specific amino acid substitution at A21, as well as a specific amino acid substitution at A4, A17, B13 or B21. U.S. Pat. No. 5,164,366A discloses an insulin analogue having amino acid deletion at one of positions B24, B25, B26 and B27. Chinese Patent CN1195777C discloses an insulin analogue having substitutions at positions A8, A9, A10, and B30. U.S. Pat. No. 7,193,035B2 discloses a crystalline insulin analogue having a substitution at position B3 and at least one substitution at one of positions B27, B28 and B29. Chinese Patent Application CN1780854A discloses an insulin analogue of A0 (Arg), A21 (Gly), B31 (Arg), and B32 (Arg).
Nevertheless, in order to achieve a better modification effect, to get a better efficacy, to decrease the binding activity between drugs and insulin-like growth factor-1 (IGF-1) receptor, and to provide more selective drugs, additional modified insulin analogues are still required for the treatment of diabetes.